Astemizole is an antagonist of the H-1 histamine receptor protein, which mediates the response antagonized by conventional antihistamines. Astemizole is well absorbed but is extensively metabolized. See Uchiyama et al., Pharmacometrics, 40:7793 (1990). Three main metabolites have been identified, all of which are reported to have some antihistamine activity. See Kamei et al., Arzneimittel-Forschung/Drug Research, 41:932-36 (1991).
Weintraub et al., Hosp. Formul., 22:918-27 (1987) describes clinical efficacy of astemizole in the treatment of both seasonal and perennial allergies. It has also been suggested that astemizole would be useful for the treatment of asthma.
Astemizole is sold commercially as a prescription antihistamine (HISMANAL.RTM.), however, the use of astemizole is believed to have a potential for serious cardiotoxicity in certain patients. Norastemizole, one of the metabolites of astemizole, is said to have the beneficial effects of astemizole while having a reduced risk of cardiotoxicity. The preparation of norastemizole is described, e.g., in WO 94/07495, published Apr. 14, 1994.
Leukotrienes augment neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increase capillary permeability, and smooth muscle contraction, all of which contribute to inflammation, edema, mucus secretion, and bronchoconstriction. For example, zileuton, sold commercially as ZYFLO.RTM., is a specific inhibitor of 5-lipoxygenase having the chemical name (.+-.)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is known to inhibit leukotriene (LTH.sub.4, LTC.sub.4, LTD.sub.4, and LTE.sub.4) formation in vitro. Zileuton is an inhibitor ex vivo of LTB.sub.4 formation in several species and inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. One study of 373 patients indicated that 600 mg of zileuton four times daily were required to provide efficacy, while 400 mg failed to do so. In some patients, zileuton was reported to cause headache, pain, asthenia, dyspepsia, nausea, and myalgia. [Physician's Desk Reference, 52 ed., Medical Economics Co., Inc., 474-76 (1998)].
Zafirlukast, sold commercially as ACCOLATE.RTM., is another type of leukotriene inhibitor. This leukotriene inhibitor is a leukotriene receptor antagonist (LTRA) of leukotriene D.sub.4 and E.sub.4, and has the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylmethyl)-3-methoxy-N-o -tolylsulfonylbenzamide. Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma. In vitro studies indicated that zafirlukast antagonized the contractile activity of three leukotrienes in conducting airway smooth muscle from laboratory animals and humans; prevented intradermal LTD.sub.4 -induced increases in cutaneous vascular permeability; and inhibited inhaled LTD.sub.4 -induced influx of eosinophils into animal lungs. In some patients, zafirlukast has been reported to cause headache, infection, nausea, diarrhea, pain, asthenia, abdominal pain, dizziness, myalgia, fever, vomiting, SGPT elevation, and dyspepsia. [Physician's Desk Reference, 52 ed., Medical Economics Co., Inc., 3148-49 (1998)].